1. Field of the Invention
The invention relates to a process for production of steroid crystals, whose average particle size is in a predetermined range and whose maximum particle size does not exceed a predetermined value, to the steroid crystals obtained thereby and to the pharmaceutical preparations containing them, especially to low-dosage preparations.
2. Description of the Related Art
Most steroids are crystallized from a suitable solvent. A large-particle-sized crystallizate is produced in a conventional cooling or displacement crystallization. This crystallizate is micronized in a jet mill to obtain the required uniformity of effective-ingredient distribution (CUT) and dissolution kinetics, especially for low-dosage preparations. Average grain sizes of from 1.5 to 5 μm are obtained. An enormous increase in surface area as well as a thermodynamic activation of the surface occurs by partial amorphization and/or by considerable destruction or perturbation of lattice structure. A series of disadvantages are connected with this process, which are described in the literature (Thibert and Tawashhi: “Micronization of Pharmaceutical Solids”, MML Series, Volume 1, Ch. 11, pp. 328–347). These disadvantages can be expressed strongly with different active ingredients. The effective ingredient can be strongly destablized by the partial amorphization. Chemical decomposition increases during interaction with the adjuvant substances in the pharmaceutical composition. An unstable physical structure is produced by recrystallization of the amorphous components. This leads to impairment of the dissolution properties and changes in the particle sizes during the precipitation of the effective ingredient, and also during preparation of the pharmaceutical composition. Agglomeration and incrustation occur during micronization, which leads to an undesirable particle size distribution in the micronizate. The particle size can be influenced only to a very limited degree during micronization. Lowering the milling pressure of course leads to a slight increase in the average particle size, but also to an undesirable increase in its spread. However a certain minimum pressure is absolutely required for operation of the mill.
Micronization as a process is only conditionally suited for manufacture of a physically and chemically stable steroid effective ingredient with a particle size adjusted to fit a certain dosage range. This is also true for alternative methods, such as manufacture of micro-fine effective ingredients from supercritical gases (Steckel, et al, “Micronizing of Steroids for Pulmonary Delivery by Supercritical Carbon Dioxide”, Int. Journal of Pharmaceutics 152, pp. 99–110 (1997)). These methods are technologically demanding and very expensive because of the high pressures. Spray-drying (Wendel, et al, “An Overview of Spray-Drying Applications”, Pharmaceutical Technology, October 1997, pp. 124–156) is similarly suitable for production of micro-fine particles, however there is a danger of producing unstable amorphous or partially crystalline structures.
It is known from the literature that fine grain size crystals can be produced by precipitation from highly supersaturated solutions or with high stirring speeds. (B. Yu. Shekunov, et al, “Crystallization Process in Pharmaceutical Technology and Drug Delivery Design”, Journal of Crystal Growth 211, pp. 122–136 (2000); Halasz-Peterfi, et al, “Formation of Microparticles of Pharmaceuticals by Homogeneous Nucleation”, Industrial Crystallization, 1999, pp. 1–11; Affonso, et al, “Microcrystallization Methods of Aspirin”, Journal of Pharmaceutical Sciences, October 1971, pp. 1572–1574).
A suitable method for producing microcrystals by rapidly cooling and intensive mixing is described in U.S. Pat. No. 3,226,389. However these crystallizates often have a large scatter and particle size agglomerates are obtained. Also the desired production of a certain particle size distribution is only possible with difficulty because of the complex interplay of super-saturation, primary and second nuclei formation and crystal growth and/or agglomerate formation.
An additional possibility for producing a definite grain size spectrum of micro-fine steroid crystals, which depends on a mechanical procedure, is described in WO A 92/08730. A crystallizate is produced from a ternary mixture, which comprises a hydrophilic solvent, a lipophilic solvent and a surfactant, by cooling in this procedure. It is indeed finer than the starting material, however the low-dose preparation is still too coarse for many applications and the same disadvantages are present, which accompany crystallizates made from highly supersaturated solutions. Contamination of the effective ingredient with surfactant also occurs.
In EP 0 522 700 the possibility, which is part of the state of the crystallization arts, for providing seed crystals for crystal growth by further definite cooling and heating of a partial flow, which is fed back into the crystallization process is described. With this procedure a grain size increase is obtained in the first place to a grain size largely above 100 μm, in order to improve the filtration and growth processes to obtain a high purity.
The influence of particle size and form on the CUT-value for spherical particles in solid drugs is described in M. C. R. Johnson, “Particle Size Distribution of Active Ingredient for Solid Dosage Forms of Low Dosage”, Pharmaceutica Acta Helvetiae, 47, pp. 546–559 (1972) and considering other forms in P. Guitard, et al, “Maximum Particle Size Distribution of Effective Ingredients for Solid Drugs in low dosage”, Pharm. Ind. 36, Nr. 4 (1974). The maximum particle dimensions related to the respective dosages can be calculated from the relationships described therein.
The dissolution kinetics is another important parameter for evaluating or rating the usually only slightly water-soluble steroid microcrystals.
The pharmaceutical performance must be continuously tested by suitable standard tests. The same goes for stability of the microcrystals as active ingredients and in pharmaceutical preparations.
The isolation and drying procedures in all the described processes for producing microcrystals in suspensions for low dose preparations can be criticized. It is very difficult to dry fine-grained moist crystallizates, without impairing the grain size distribution.